During the period covered by this report we have been concerned with the factors that make nucleosides and analogous molecules selectively damaging to unwanted invaders with minimal injury to normal cells. Factors that determine the angles made by the glycosidic bond are critical. It is significant that for these molecules their effectiveness depends almost uniformly on their being in the high anti or anti conformation. The factors that influence this and can be manipulated are charges on such atoms as N3 and N8 in the purines and the intrinsic effect of the 2'-OH group in arabinosyl analogs. There is experimental evidence consistent with our theoretical considerations that deoxycytidine kinase and adenosine kinase both require substrates in the high anti conformation. The orientation of the base moiety relative to the ribose moiety in cyclic nucleotides also determines the magnitude of cyclic nucleotide effects. The formation of cyclic AMP by adenylate cyclase requires a high anti orientation in adenosine analogs that stimulate cAMP formation. Protein kinase II is activated by cyclic nucleotide analogs in an anti conformation. The design of selective drugs and the control of cyclic nucleotide dependent physiological processes are both dependent on a correct understanding of nucleoside conformation. Experimental and theoretical investigations are being made to further define and extend such relationships.